chr11-2572981-G-C
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.916G>C(p.Gly306Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.916G>C | p.Gly306Arg | missense_variant | 6/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.916G>C | p.Gly306Arg | missense_variant | 6/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.535G>C | p.Gly179Arg | missense_variant | 6/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.655G>C | p.Gly219Arg | missense_variant | 7/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-10454G>C | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Nov 03, 2022 | We observed a c.916G>C (p.Gly306Arg) genetic variant in the KCNQ1 gene on WES data in a 11-y.o. male proband, manifested with syncope during swimming and QTc prolongation up to 475 ms. This variant is not present in gnomAD database and located in a mutational hot spot and/or critical and well-established functional domain (PM1_strong according to Walsh R. et al. (PMID: 32893267). Multiple computational resources predict deleterious effect of p.Gly306Arg genetic variant. An alternative genetic variant c.916G>A (p.Gly306Arg) has been reported as pathogenic and associated with Long QT syndrome. Based on this evidence, we consider it to classify the c.916G>C (p.Gly306Arg) variant as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2023 | Published functional studies demonstrate a dominant negative effect (Li et al., 2001; Wang et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with LQTS in published literature; however, detailed clinical information was not provided (Andrsova et al., 2012; Zareba et al., 2003; Moss et al., 2007; Jons et al., 2009; Kapplinger et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 22456477, 15234419, 17470695, 19490272, 22727609, 32431610, 11351021, 10376919, 14678125) - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085;PMID:10376919;PMID:11351021). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at